N-phenyl amidines

ABSTRACT

N-Phenyl amidines which have diuretic, antithrombogenic, smooth muscle relaxant, anti-inflammatory and antiarrhythmic properties have been discovered. They are prepared by reacting a substituted aniline with a carboxamide selected from the group consisting of amides and lactams in the presence of phosphorus oxychloride. Typical examples of substituted N-phenyl amidines thus obtained are 5-methyl-2-(N-phenylbenzylamino)-1-pyrroline, 2-(Nphenylbenzylamino)-1-pyrroline, 3-((N-1-pyrrolin-2-yl-panisidino)methyl)indole and 4,5,6,7,8,9-hexahydro-2-(Nphenylphenethylamino)-3H-azonine. Indole substituted N-phenyl amidines can be rearranged to provide iminopyrrolidinylindoles which are useful as diuretic, antithrombogenic and smooth muscle relaxant agents. In the case of 3-((N-1-pyrrolin-2-yl-panisidino)methyl)indole, the rearranged product is 3-((2-(pmethoxyphenylimino)-1-pyrrolindinyl)methyl)indole.

United States Patent Pfister' Dec. 23, 1975 [54] NOVEL SUBSTITUTED XANTHONE [56] References Cited CARBOXYLIC ACID COMPOUNDS UNITED STATES PATENTS [75] Invent Julg Pfister L05 Altos; 3,642,997 2/72 Shen etal ..424 250 Harrison; J Fried, both 5,795,758 12/72 Bays ..260/335 of Palo Alto; all of California Assigneei Symex P310 Alto, Primary ExaminerNorma S. Milestone Calif. Attorney-Gerard A. Blaufarb, Walter H. Dreger, [22] Filed: Feb. 7 1974 and Wllllam B. Walker [21] Appl. No.:440,327 I Related U.S. Application Data v [57] ABSTRACT Division of Ser. No. 259671 June 5 1972; now Com g positions containing and methods employing, 3 321252 whlch a contmuanon' as the essential ingredient, novel substituted xanthone in-part of Ser. No. 231,756, March 3, 1972, now l abandoned carboxylic acid compounds WhlCh are useful in the treatment of allergic conditions; Methods for pre- [52] U.S. Cl. 424/278, 260/293.58; paring these compounds and compositions and inter- 260/268; 211 mediates therein are also disclosed. 6-Acetyl-xan- [51] Int. Cl. C07D, 311/86 thone-2-carboxylic acid is illustrated as a representative compound.

Field of Search 260/335 4 Claims, No Drawings NOVEL SUBSTITUTEDXA NTHONE v 5 CARBOXYLIC ACID COMPOUNDS I, v g i 1 This is adivision of application Serial No. 259,671 filed June 5, 1972, HOW us. Patent No. 3,821,252 5 which is a continuation-in-part of application Serial (D) No. 231,756 filed March 3, 1972, now abandoned.

The present invention is directed to novel substi- (4) The (1-6 lower alkylsulfon'yl substituted xantuted xanthone carboxylic acid compounds and to thone- Z-carboxylic' acid compoundsof the formula;

compositions containing and methods utilizing these 1 compounds as the essential ingredient in the treatment of symptoms associated with allergic manifestations, forexample, asthmatic conditions.

In a first aspect, the present invention relatesto novel C-6 substituted xanthone-Q-carboxylie acid 1 0 compounds selected from those represented by the following formula: i

. mono R o I y (I l i and the pharmaceutically acceptable, non-toxic esters, I i amides and salts thereof: wherein R is a group selected (5) The C6V sulfo substituted xanthon e-Z-carboxylic acid compounds of the formula:

fmmthose oftheformulas (6) TheC -6 sulfamoyl, N-monolower alkylsuls,

" I famoyl, and N,N-dilower alkylsulfamoyl substituted grfi 7 2 xanthone-Z-carboxylic acid compounds of the. formula:

(wherein R is hydrogen, lower alkyl, cycloalkyl, coo

tetrahydrofuran-Z-yl, tetrahydropyran-Z-yl, tetrai i hydropyran-4-yl, 4-alkoxytetrahydropyrana4-yl, or 8 I carboxylic acyl containing up to ;l2 carbon atoms, G h i 0 I and each of R and-.Rfis hydrogen; lower alkyl; cyclo- 6 alkyl; phenyl; substituted phenyl, in which the sub- (6) stituent' is halo, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, or cyano; or a monocyclic aromatic heterocyclic group having five or six total members, one or two of which are selected from nitrogen, oxygen, and sulfur); lower alkylsulfinyl; lower alkylsulfonyl: sulfo; sulfamoyl; monolower alkylsuland each of hydmgelh or W f famoy]; or dilower alkylsulfamoyl. In a second aspect, the present invention is directed Thus included within the scope of the present invena methqd usefill for iehevmg symptoms assoclated tion are (I) The l hydmxyalkyl Substituted with allergic manifestationssuch-as are brought about xanthone z carboxylic acid compounds f ,the by antigen-antibody (allergic)reactions. In the rel ef of these symptoms, the method hereof serves to in- 0 and the pharmaceutically acceptable, non-toxic esters, amides and salts thereof; wherein each of R, R and R is as above defined, R being preferably hydrogen, methyl or acetyl, each of R and R is lower alkyl,

formula I hibit the effects of the allergic reaction when administered in an effective amount. While not intending to 90H be bound by any theoretical mechanism of action,

i Y the method hereof is believed to operate by inhibiting t -Q" V I 'the release and/or the action of toxic products, e.g.,

histamine, S-hydroxytryptamine, slow releasing (a) substance (SRS-A), and others, which are produced as a result of a combination of specific antibody and ggzgg g f z g; ggigi fifif f antigen (allergic reaction). These properties make the v subject compounds particularly useful in the treatment o of various allergic conditions.

coor-i This aspect of the present invention thus relates to a method useful for inhibiting the effects of the aller- 2 2 v gic reation which comprises administering an effective amount of a compound selected from those represented by the above formula (A) or a pharmaceutically acceptable non-toxic composition incorporating (3) The C-6 lower alkylsulfinyl substituted xansaid acids, esters, amides or salts as an essential thone-Z-carboxylic acid compounds of the formula: ingredient.

The present invention, in a third aspect, is directed to pharmaceutical compositions useful for inhibiting the effects of the allergic reaction comprising an effective amount of a compound selected from those represented by the above formula (A) in admixture with a pharmaceutically acceptable non-toxic carrier.

The compounds of the present invention are also smooth muscle relaxants, e.g. bronchial dilators, and are therefore useful in the treatment of conditions in which such agents may be indicated, as for instance in the treatment of bronchio constriction. The compounds of the present invention are also vasodilators and are therefore useful in the treatment of conditions in which such agents may be indicated, as for instance in renal and cardiac disorders.

In the practice of the method of the present invention, an effective amount of a compound of the present invention or pharmaceutical compositions thereof, as defined above, is administered via any of the usual and acceptable methods known in the art, either singly or in combination with another compound or compounds of the present invention or other pharmaceutical agents, such as antibiotics, hormonal agents, and so forth. These compounds or compositions can thus be administered orally, topically, parenterally, or by inhalation and in the form of either solid, liquid, or gaseous dosages including tablets, suspensions,-and aerosols, as discussed in more detail hereinafter. The administration can be conducted in single unit dosage form with continuous therapy or in single dose therapy ad libitum. In the preferred embodiments, the method of the present invention is practiced when relief of symptoms is specifically required, or perhaps, imminent: however, the method hereof is also usefully practiced as continuous or prophylactic treatment.

In view of the foregoing as well as in consideration of the degree or severity of the condition being treated, age of subject, and so forth, all of which factors being determinable by routine experimenta tion by one skilled in the art: the effective dosage in accordance herewith can vary over a wide range.

Generally an effective amount ranges from about 0.005 to about 100mg. per kg. of body weight per day and preferably from about 0.01 to about 100 mg. per kg. of body weight per'day. In alternate. terms, an effective amount in accordance herewith generally ranges from about 0.5 to about 7000 mg. per day per subiect.

Useful'pharmaceutical carriers for the preparation of the compositions hereof, can be solids, liquids, or gases. Thus, the compositions can take the form of tablets, pills, capsules, powders, sustained release formulations, solutions, suspensions, elixir's, aerosols, and the like. The carriers can be selected from the various oils including those of petroleum, animal,

vegetable, or synthetic origin, for example, peanut glycol, water, ethanol, and the like. Suitable pharmaceutical carriers and their formulation are described in Remingtons Pharmaceutical Sciences by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable amount of carrier so as to prepare the proper dosage form for proper administration to the host.

The compounds of the present invention demonstrate activity as inhibitors of the effects ofthe allergic I reactionas measured by tests-indicative of such coon CI Q eL l v V activity involving passive cutaneous anaphylaxis as substantially described, for example, by J. Goose et al.,ImmunoIogy, 1 6, 749 (1969). I

Certain of the compounds of the present invention can be prepared in accordance with the following reaction sequence:

' Segucncc A and each of R, R and R is lower alkyl, preferably methyl.

R being t wherein each of R. R and R is as above defined;

With reference to the above reaction sequence,.-

para-methyl phenol (2) is condensed with the 2,4- dichlorobenzoic acid (1) in the presence of copper powder with anhydrous potassium carbonate, optionally in organic liquid reaction medium, preferably an organic amide such as dimethyl acetamide-, dimethylformamide, N-methylpyrrolidone, tetramethyl- The 6-methoxyxanthone-l-carboxylic acid com pound (7) thus prepared is converted to the respective 6-liydroxy" compound by'treatment with hydrobromic o'r hydroiodic acid and acetic acid. This reaction is conducted .at a temperature of from about l to about 160C followed by esterification (R7) to give urea, and so forth, to prepare the corresponding 2- (p-methylphenyloxy)-4-chlorobenzoic acid compound The reaction is preferably conducted in an inert organic reaction medium, such as those listed above, or suitable mixtures of one or more of such media. The reaction is further conducted at temperatures ranging from about 80 to about 220C, preferably from about 120 to 200C and for a period of time sufficient to complete the reaction, ranging from about 2 hours to about 24 hours. i

The reaction consumes the reactants on the basis of one mole of the substituted phenol per mole of the. dichlorobenzoic acid. However. the amounts of the; reactants to be employed are not critical, some of the, desired compound (3) product being obtained when employing any employing any proportions thereof. In the preferred embodiments, the reaction is conducted by reacting from about I to about 3 moles of the substituted phenol compound with about from" I to about l.2 moles of the dichlorobenzoic acid compound in the presence of catalytic amounts of the copper powder. The inert organic reaction med-'-"' ium, if employed, is used in solvent amounts.

Thereafter, the prepared compound (3) is oxidized with potassium permanganate in aqueous t-butanol to give the corresponding 2-(p-carboxyphenyloxy)- 4-chlorobenzoic acid (4).

The thus-prepared diacid compound (4) is then cyclized with phosphoryl chloride, thionyl chloride, sulfuric acid, hydrogen fluoride, or, preferably, polyphosphoric acid (PPA) to give the corresponding 6- chloroxanthone-Z-carboxylic acid compound (5). The

reaction is preferably, but optionally, conducted in compounds (8). This reaction 3 is conducted with ethereal diazoalkane such as diaxomethane and diazoethane or with the desired lower alkyl iodide in the presence of lithium carbonate at room temperature or with the desired lower alkanol in the presence of a trace of sulfuric acid at reflux.

The hydroxyacid esters (8) are then treated with [a diallkylthiocarbamoyl chloride, such as dimethylby reaction of from about I.) to about 1.5. moles of dialkylthiocarbamoyl chloride per mole of compound The product compounds (9) are then rearranged by reaction at a temperature of from about 200 to about 250C, preferably from about 220 to about 230C,

..and for a period of time ranging from about I hour to about 8 hours and in the presence of organic medium such as sulfolane, nitrobenzene, triethyleneglycol, and soforth, which is preferably employed in solvent amounts, to give compound (10),

an inert organic reaction medium including those usually employed in organic chemical reactions, such as dimethylsulfoxide, sulfolane, benzene, toluene, and so forth. The reaction is further conducted at temperatures ranging from about 60 to about 180C, and for a period of time sufficient to complete the reaction ranging from about 15 minutes to about 90 minutes.

Although the reaction consumes the reactants on the basis of one mole of compound (4) per mole of cyclizing reagent, the reaction can be performed using any proportions of reactants. In the preferred embodiments, however, the reaction is conducted using from about 20 to about moles of the cyclizing reagent per mole of starting compound (4). y

The 6-chloroxanthone-Z-carboxylic acid (5) is then treated with excess alkali metal lower alkoxide e.g., sodium methoxide to give compound (7) or with excess alkali metal thioloweralkoxide to give compounds (6). The reaction is preferably conducted in polar organic solvent at temperatures of from about 80 to about l50C.

6 this type, e.g. aqueous alkanol solutions.

Compounds (10) are then converted to the corresponding 6-mercapto acid compounds (I l) by base hydrolysis using an alkali metal hydroxide at about 50 to about 90C and for a period of time sufficient to complete the reaction, ranging from about 15 minutes to about '60 minutes, preferably in the presence of inert organic reaction media such as those normally employed in organic chemical reactions of The 6-lower alkylthio ether, ester compounds can 'be prepared by reacting compounds (1 l) with a lower alkyl halide in the presence of base such as potassium carbonate and organic liquidreaction media such asthose described above. The reaction is conducted at a temperature ranging from about 20 to about 80C, preferably from 50 to about C and for a-period of time sufficient to complete the reaction, ranging from about 2 hours to about 16 hours. Hydrolysis ofthe ester, if desired, affords the 6- (lower alkylthio)-acid compounds (6).

Compound (6) is esterified" to the acid ester, or the acid ester thereof prepared as described above, can be oxidized with a peracid, such as peracetic ,-acid,v m-chloroperbenzoic acid, p-nitroperbenzoic acid, perphthalic acid, and so forth, to give compounds (l'2)Iwhich can be hydrolyzed, as above .65"

described, to" give the corresponding 6-lower alkylsulfinyl acid compounds (D). The oxidation is preferably conducted in liquid reactionmedia such as a chlorinated hydrocarbon, e.g. chloroform, methylene chloride, and carbon tetrachloride. The reaction is conducted at temperatures ranging from about 0 9 to about 60C, preferably from 20tof about 30C and for a period of time sufficient"to"complete the reaction, ranging from about 1 hour to about 6 hours. In the preferred embodiments, the reaction is conducted by reaction of from about 1 to about 1.] moles of peracid.

Alternatively, the acid esters of compounds (6) are oxidized with excess hydrogen peroxide to give compounds (13) which can be hydrolyzed as above described to give the 6-lower alkylsulfonyl acid com pounds (E). The peroxide oxidation is preferably conducted in liquid reaction media such as a lower conditions and at a temperature ranging from about carboxylic acid, e.g. acetic acid and propionic acid.

employing peracid, a mixture of products (12) and (13) may be obtained. If obtained, the mixture can be conventionally separated, such as via chromatography, if desired, to isolate the oxidized products. The above oxidation steps can also be practiced on the acid starting compounds (6) to give respective products (D) or (E) without the need of a second hydrolysis step. Q

e---- I I 9 0 Alternatively, compounds (11) can be treated with excess chlorine under acidic conditions to afford compounds (14). This reaction is conducted employing a 20 to about 100C, preferably from 80 to about 90C and for a period of from about I hour to about 2 hours to give the 6-sulfo-substituted acid compounds (F).

Compounds (14) can be treated with ammonia, monolower alkylamine, or dilower alkylamine to give the 6-sulfamoyl, monolower alkylsulfamoyl, and dilower alkylsulfarnoyl acid compounds (G). This reaction is conducted at temperatures ranging from about 0 to about 80C, preferably from 20 to about 30C, and for a period of time sufficient to complete the reaction, ranging from about 1 hour to about 8 hours. In the preferred embodiments, the reaction is conducted by reaction of from about 10 to about 20 moles of amine per mole of compound (14). This reaction is further conducted in organic reaction media such as those described above, preferably tetrahydrofuran, dioxane, dimethylsulfoxide, and so forth.

The 6-chlorosulfonylxanthone-2-carboxylic acid compound (14), as. well as 6-mercaptoxanthone-2-carboxylic acid and the 6-lower alkylthioxanthone-Z- carboxylic acid compounds hereof, are novel intermediates useful as described above.

Alternatively, certain of the compounds of the present invention can be prepared in accordance with the following: l

- Segnonce B I coon a i COOII COOK I wherein R is lower alkylt'hio, or chloro;

R is as defined above; and

halo is bromo, chloro, fluoro, or iodo, preferably pH of about 1 by use of hydrochloric acid, optionally bromo.

in acetic acid solution. The reaction is further conducted at temperatures ranging from about 20 'to about 100C, preferably from to about C and for a period of time sufficient to complete the reaction, ranging from about 2 hours to about 12 hours.

Compound (14) is then reacted with a base, such as alkali metal hydroxide, preferably under aqueous Certain compounds hereof are prepared as" illustrated by the following sequence:

'12" are reduced with sodium borohydride to give the 6- (secondary hydroxyalkyD-xanthone-Z-carb0xylic acid Scgucnce, C

i t R CH- s 0H 1 I I 7 I COOR O I l l R -CH O 7 i7 7 cooR 7 (15) COOR COOK COO Z i 1O I Q 10 I V. I I R "CH 0 R .cnz O .a v A 1 coon o coon a I I "r a -c 0 a -cn o wherein R is lower alkyl; and a each of R, R R and halo is as above defined. With reference to the above reaction sequence, the V 6-substituted-xanthone-2carboxylic compounds (23) are prepared following the above reaction Sequence- B (15+ l6 17 l8- 19) with the respective starting compounds (20). I

The resultant compounds (23), or their esters, are oxidized with chromium trioxide in acetic acid-acetic anhydride to give the 6-acyl compounds (C) which products (D). Alternative to the above procedure, the 6-substituted xanthone-Z-carboxylic acid (23) can be converted to its corresponding ester and it treated with N-bromosuccinimide to prepare the corresponding 6-(substituted bromoethyl) compound (i.e. R H-Br) which can be converted to the corresponding alcohol upon treatment with aqueous base, to give the product acids (B).

Certain of the compounds hereof can be prepared as follows:

wherein R is as definediabove.

In the above Sequence, compounds (24) and are condensed as described above, e.g. l 2 3', to give the diacid compound() which is cyclized'as described, e.g. 4- 5, togive compound (7) which is useful as depicted and described in Sequence Aabovej An alternative method for the preparation of cer-" tain of the compounds hereof is represented a such method involves treating the products repre-" sented by Formula (B) with a carboxylic acid-chloride or carboxylic acid anhydridehin the presence of a" base, preferably pyridine, at temperatures ranging} from'about 60 to about 90C andfor a periodof time ranging from about one to about two hours to give the corresponding secondary carboxylic acyloxy alkyl substituted "XanthoneQ-carboxylic acid compound.-

follows: x 10 The alkyl and cycloalkyl ethers of the secondary Soguence- E R on i I J (16) I v ca J 2 R9 O l/ (2 7) CH3 halo I coon 1 g I, V h cool I IL I 9 .9 .0 R o R (19) (m) coon wherein R and halo are as defined above. hydroxyalkyl series (R' alkyl, cycloalkyl) are pre- With reference to" Sequence E, an appropriate phenol (16) is treated with I',3-dimethyl-4-halo (preferably iodo)-benzene (26), as describedabove;

to prepare the corresponding 1,3-dimethyl-4-phenyloxybenzene (27). This coinpoundis then'oxidized such as with potassium permanganate in aqueous t-butanol, as described above, eg 3 4, to give (18) which is then cyclized,as described above, to give the corresponding xanthone-2-earboxylic acid (19) useful as described above to prepare the compounds of the present invention.

Certain of the compounds hereof in the 6-hydroxyalkyl and 6-acyl seriesfcan be prepared by treating acetanilide with an appropriate acid chloride, e.g.

benzoyl chloride, to give the corresponding p-acyl-" acetanilide compoundjconverting the latter with dilute mineral acid to p-acylar'iilin'e. The'latter is treated with bromine to give the corresponding o-bromo-p-acylaniline which, when treated' 'with sodium-nitrite and sodium fluoroborate followed by treatment with nickel carbonyl, gives the corresponding o-bromo-p-acylbenzoic acid. The latter is esterified and reacted with p-hydroxybenz'oate followed by hydrolysis and cycliz ation, all as described above, to give the" 6-acylxantlione-2-earboxylic acid compounds. Reduction of the acyl group, as described above, affords the corresponding 6-hydroxyalkyl compounds.

The carboxylicacyl'e'sters of the hydroxy'alkyl substituted compounds (i.'e. R=carboxylic acyl) .are prepared as' described above or by secondary alcohol esterification methods known per se; One

pared by treatment of the 'xanthone acid'ester with'the' appropriate alkylor cycloalkyl halide and sodium hydride in, e.g. 'dimethylformamide, followed by hy drolysis, as described above. The etherific ation reaction is conducted at from about 50 to about C and for from about one to about five hours. i 'The t-butoxy' ethers are prepared by treating the alcohol with isobutene in the presence "of boron trifluoride and phosphoric acid in, e.g. methylene chloride, at temperatures of from about'l0 to about 30C and for from 10'to about'24 hours, or more, followed by hydrolysis of the acid ester group, as described above.

The tetrahydrOfuran-Z-yloxy and tetranydropyran- 2 -yloxyethers of the hydroxyalkyl compounds are prepared by treatment with dihydrofuran or dihydropyran' in the presence of p-toluenesulfonic acid and organic'reaction medium, e.g. benzene,at about room temperature up to reflux, for from about two to about fivedays, followed by hydrolysis of the acid ester, as described above. t

The 4-alkoxytetrahydropyran-4-yloxy' ethers are prepared by treatment of the alcohol with 4-alkoxy- 5,6-dihydro-2l-l-pyran, as described above for'the preparation of the furanyl and pyranyl ethers, followed by acid ester hydrolysis. Treatment of the 4- alkoxytetrahydropyran-4-yloxy ether with aluminum chloride and lithium aluminum hydride in organic reaction medium affords the corresponding tetrahydrop'yran-4-yloxy ethers which are oxidized to give the corresponding ethers in the xanthone acid series. The latter can be directly prepared by treating the alcohol with 4-br0motetrahydropyran and base.

kanol in the presence of a' trace of sulfuric acid at reflux. The glycerol esters are prepared by treating the acid with thionyl chloride followed by treatment with a suitably protected ethylene glycol or propylene glycol (e.g. solketal) in pyridine, and hydrolyzing' the protecting group of the ester thus formed with dilute acid.

The amides of the xanthone-2-carboxylic acids hereof are prepared by treatment of the acids with thionyl chloride followed by treatment with anhydrous ammonia, alkyl amine, dialkyl amine, dialkylaminoalkylamine, alkoxyalkylamine, or phenethylamine.

The salts of the xanthone-2-carboxylic acids hereof are prepared by treating the corresponding acids with a pharmaceutically acceptable base. Representative salts derived from such pharmaceutically acceptable bases include the sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, ferric, zinc, manganous, aluminum, manganic, trimethylamine, triethylamine, tripropylamine, ,B-(dimethylamino)- ethanol, triethanolamine, ,B(diethylamino)ethanol, arginine, lysine, histidine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methyl glucamine, theobromine, purines, piperazine, piperidine, polyamine resins, caffeine, procaine salts. The reaction is conducted in an aqueous solution, alone or in combination with an inert, watermiscible organic solvent, at a temperature of from about C to about 100C, preferably at room temperature. Typical inert, water-miscible organicsolvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane, or tetrahydrofuran. When divalent metal salts are prepared, such as the calcium salts or magnesium salts of the acids, the free acid starting material is treated with about one-half molar equivalent of pharmaceutically acceptable base. When the aluminum saltsof the acids are prepared, about onethird molar equivalent of the pharmaceutically ac- In the preferred embodiment of the presentinvenv tion, the aluminum salts of the acids are prepared by treating the acids with at least one-third molar equivalent of an aluminum alkoxide, such as aluminum triethoxide, aluminum tripropoxide, and the like, in a hydrocarbon solvent, such as benzene, xylene, cyclohexane, and the like, at a temperature of from 20C to about 115C. I v

In the sulfo series, use of one equivalent of base provides the sulfo acid monosalts; use of two equiva lents provides the disalts.

The starting compounds for use in the present invention are known and can be prepared in accordance with known procedures. Thus, the 1,3- dicarbo(lower)alkoxy-4-halobenzene starting compounds are conveniently, prepared by oxidizing 1,3- dimethyl 4-halobenzene(4halo-m-xylene) with potassium permanganate, as described above, followed by conventional esterification. Lower alkoxyphenylcarboxylic acid chloride acylating agents for the preparation of alkoxyphenylcarbonylacetanilide starting compounds, are prepared, for example, by selectively esterifying *hydroxybenzoic acid with methanol and a trace of sulfuric acid or with lithium carbonate and methyl halide in dimethylformamide' The resultant hydroxybenzoate ester is then conventionally alkylated with lower alkylhalide and potassium carbonate followed by selective hydrolysis of the ester of the carboxylic acid group and conversion to the acid chloride with, e.g. thionyl chloride.

In the present specification and claims, by the term lower alkyl is intended a lower alkyl group containing one to eight carbon atoms including straight and branched chain groups, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tbutyl, n-pentyl, isopentyl, sec-pentyl, t-pentyl, nhexyl, n-pentyl, n-octyl, isooctyl. The term cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. By the term lower alkoxy is intended the group O-lower alkyl wherein lower alkyl is as defined above. By the term lower alkylthio. is intended the group S-lower alkyl wherein lower alkyl is as defined above. The term substituted phenyl includes p-substituted phenyl. The term monocyclic aromatic heterocyclic group includes pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidozolyl, furanyl, thiophenyl, pyrrolyl, isoxazolyl, and oxazolyl. By the term halomethyl is meant trifluoromethyl, tn'chloromethyl, difluoromethyl, and dichloromethyl. l

By the term pharmaceutically acceptable, nontoxic esters, amides, and salts is respectively intended an alkyl or glycerol ester; an unsubstituted, monoalkyl, dialkyl, dialkylaminoalkyl, alkoxyalkyl, or phenethyl substituted amide and a salt as defined above.

The term carboxylic acyl, as used herein, refers to those physiologically acceptable acyl groups, conventionally employed in the pharmaceutical art, preferably hydrocarbon carboxylic acyl. Included are acetate,.propionate, butyrate, trimethylacetate, valerate, methylethylacetate, .caproate, t-butylacetate, 3- methylpentanoate, enanthate, ..caprylate, triethylacetate, pelargonate, decanoate, undecanoate, benzoate, phenylacetate, 'diphenylacetate, cyclopentyl- I propionate, methoxy-acetate, 'aminoacetate, diethylaminoacetate, trichloroacetate, ,B-chloropropionate,

bicyclo[2.2.2]octane-l-carboxylate, adamantoate, di-

hydrogen phosphate, dibenzyl phosphate, sodium ethyl phosphate, sodium sulfate, sulfate, and the means such as forming the alkaloid salts of the products and employing fractional crystallization. The nomenclature herein is employed in accordance with Chemical Abstracts, 56, Subject Index (1962,

January-June).

The following examples illustrate the method by which the present invention can be practiced.

EXAMPLE 1 A mixture of g. of 2,4-dichlorobenzoic acid, 10 g. of p-methylphenol, 0.5 g. of copper powder and g. of anhydrous potassium carbonate in 200 ml. of dimethyl-formamide is heated to 165C and maintained thereat with stirring and under a nitrogen atmosphere. After monitoring via tlc indicates the reaction is substantially complete, the reaction mixture is diluted with water, treated with charcoal, filtered and the clear filtrate acidified. The precipitate is isolated by suction filtration, washed neutral and dried to give 2-(p-methylphenyloxy)-4-chlorobenzoic acid.

A mixture of 12 g. of 2-(p-methylphenyloxy)-4- chlorobenzoic acid, 72 g. of potassium permanganate, 200 ml. of t-butanol and 350 ml. of water is refluxed for 4.5 hours. After this time, the t-butanol is distilled off, and the reaction mixture is filtered. The filtrate is acidified to give 2-(p-carboxyphenyloxy)-4-chlorobenzoic acid which can be recrystallized from benzene:heptane.

Two g. of 2-(p-carboxyphenyloxy)-4-chlorobenzoic acid in 20 ml. of concentrated sulfuric acid is stirred at 80C for 1 hour. After this time, the reaction mixture is poured into 200 ml. of ice water and the resultant mixture is heated on a steam bath for 15 minutes. The mixture is cooled and filtered with the precipitate being washed with water and then recrystallized from acetic acid to give 6-chloroxanthone- Z-carboxylic acid.

EXAMPLE 2 6-Chloroxanthone-Z-carboxylic acid (2.5 g.) and 1.8 g. of sodium methyl mercaptide in ml. of hexamethylphosphoramide (HMPA) is stirred for two hours at 100C. After acidification, the product is filtered off, washed with water and dried to give 6- S EXAMPLE 3 A mixture of 11 g. of 6-methoxyxanthone-2-carboxylic acid in 100 ml. of concentrated aqueous hydrogen iodide and 100 ml. of acetic acid is refluxed for 4 hours. After this time, the mixture is cooled, diluted with water, and filtered. The precipitate is washed and dried to give 6-hydroxyxanthone-2- carboxylic acid.

EXAMPLE 4 A mixture of 4 g. of 6-hydroxyxanthone-2-carboxylic acid, 10 g. of methyl iodide, and 10 g. of lithium carbonate in ml. of dimethylformamide is stirred at room temperature for a period of 16 hours. After this period of time, the reaction mixture is poured into dilute hydrochloric acid-ice and the resultant mixture extracted with ethyl acetate. The extracts are filtered through alumina to give methyl 6-hydroxy-xanthone-2-carboxylate which can be recrystallized from methanol.

EXAMPLE 5 To a solution of 6.2 g. of methyl 6-hydroxyxanthone- Z-carboxylate in 100 ml. of dimethylformamideare added 1 g. of sodium hydride. The mixture is stirred for 10 minutes at room temperature under nitrogen. Dimethylthiocarbamoyl chloride (3 g.) is then added thereto and the resultant mixture stirred at C for 6 hours and then at room temperature for 16 hours. The mixture is then poured into 200 ml. of water containing 1 ml. of acetic acid; the resultant mixture is filtered and the solid dried to give methyl 6-dimethylthiocarbamoyloxyxanthone-Z-carboxylate.

Methyl 6-dimethylthiocarbamoyloxyxanthone-Z- carboxylate (8 g.) in 150 ml. of sulfolane is stirred at 230C under nitrogen. After a total of 6 hours under these conditions, tlc indicates the absence of starting material. The mixture is cooled. to C under nitrogen. After a total of 6 hours under these conditions, tlc indicates the absence of starting material. The mixture is cooled to 80C and ml. of hot water are slowly added. The mixture is then cooled and the filtered solid washed with water and dried to give methyl 6-(dimethylcarbamoylthio)-xanthone 2- carboxylate.

Methyl 6-(dimethylcarbamoylthio)-xanthone-2- carboxylate (7.5 g.), 10 g. of potassium hydroxide and 250 ml. of 80% aqueous ethanol is refluxed for 1 hour. After this time, 250 ml. of water are addedand the mixture is treated with charcoal, filtered,acidified. The product is filtered off and dried to give 6-mercaptoxanthone-Z-carboxylic acid.

EXAMPLE 6 A mixture of 3 g. of 6-inercaptoxanthone-2 -carboxylic acid in 150 ml. of dimethylformamide, 5 ml. of methyl iodide and 5 ml. of potassium carbonate is stirred for 16 hours at 60C. The mixture is then poured into dilute hydrochloric acid and the reextracts are chromatographed on alumina (methylene chloride) to give methyl 6-(methylthio)-xanthone-Z- carboxylate (i.e. methyl 6-thiomethoxyxanthone-Z- carboxylate) which can be recrystallized vfrom methylene chloridezmethanol.

A mixture of 580 mg. of methyl h-(incth lthio)- xanthone-Z-carboxylate, 30 ml. of ethanol, ml. of saturated sodium carbonate solution and 5 ml. of water is refluxed for 1 hour. The mixture is then cooled, acidified and the precipitate filtered off to give 6-(methylthio)-xanthone-Zcarboxylic acid (i.e. 6-thiomethoxyxanthone-2-carboxylic acid) as also prepared in the alternative method described in Example 2.

A mixture of 0.8 g. of 6-mercaptoxanthone-2carboxylic acid, 2 ml. of 2-bromopropane, and excess potassium carbonate in 50 ml. of dimethylformamide' is stirred for 24 hours at 75C. Dilute hydrochloric acid and ethanol are added, the solid filtered off and Washed. The solid is saponified with sodium carbonate in aqueous methanol minutes reflux). The alkaline solution is diluted with water, treated with charcoal, filtered, and acidified to give 6-(isopropylthio)- xanthone-Z-carboxylic acid which can be recrystallized from tetrahydrofuransethyl acetate.

In a similar manner (and alternative to the method of Example 2), the following are prepared from the respective starting compounds: 6-(ethylthio)-xanthone-2-carboxylic acid, 6-(n-propylthio)-xanthone-2-carboxylic acid, 6-(n-butylthio)-xanthone{2'-carboxylic acid, 6-(sec-butylthio)-xanthone-2-carboxylic acid, 6-(isobutylthio)-xanthone-2-carboxylic acid, 6-(t-butylthio)-xanthone-2-carboxylic acid, 6-(n-pentylthio)-xanthone-2-carboxylic acid, 6-(cyclopropylthio)-xanthone-2-carboxylic acid, 6-(cyclobutylthio)-xanthone-2-carboxylic acid, and 6-(cyclopentylthio)-xanthone2-carboxylic acid.

EXAMPLE 7 Methyl 6 (methylthio) xanthone 2 carboxylate (764 mg), 2 ml. of hydrogen peroxide (30%), and ml. of acetic acid are heated on the steam bath (80C) for 90 minutes. Tlc indicates the absence of starting material. The mixture is diluted with 60 ml. of hot water, and the mixture is cooled, the solid is filtered off and dried to give methyl 6-methylsulfonylxanthone- 2-carboxylate which can be recrystallized from acetic acidzwater.

Methyl 6-methylsulfonylxanthone-2-carboxylate (660 mg.), 1 g. of potassium hydroxide, and 60 ml. of 80% aqueous ethanol are refluxed for 30 minutes. The mixture is filtered, acidified, and the solid filtered off to give 6-methylsulfonylxanthone-Z-carboxylic acid.

Likewise, from the respective starting compounds are prepared the following compounds: 6-isopropylsulfonylxanthone-Z-carboxylic acid, 6-ethylsulfonylxanthone-2-carboxylic acid, 6-n-propylsulfonylxanthone-Z-carboxylic acid, 6-n-butylsulfonylxanthone-Z-carboxylic acid, 6-sec-butylsulfonylxanthone-Z-carboxylic acid, 6-isobutylsulfonylxanthone-2-carboxylic acid, 6-t-butylsulfonylxanthone-Z-carboxylic acid,

20 6-n-pentylsulfonylxanthone-Z-carboxylic acid, 6-cyclopropyl'sulfonylxanthone-Z-carboxylic acid,

6 cyclobutylsulfonylxanthone-Z-carboxylic acid, and

6-cyclopentylsulfonylxanthone-2-carboxylic acid.

EXAMPLE 8 Methyl 6-(methylthio)-xanthone-2-carboxylate (927 mg.) in ml. of methylene chloride is cooled to 0C (ice). m-Chloroperbenzoic acid (555 mg.) is then added and the mixture is stirred at 0C for minutes. The reaction mixture is then filtered through alumina and the column washed with methylene chloride to give methyl 6-methylsulfinylxanthone-2-carboxylate which can be recrystallized from benzenezheptane.

Methyl 6 methylsulfinylxanthone 2 carboxylate (720 mg), 75 ml. of ethanol, and 10 ml. of 5% sodium hydroxide are refluxed for 30 minutes. The mixture is cooled, partially evaporated and acidified. The precipitate is filtered off, washed and dried to give 6-methylsulfinylxanthone-Z-carboxylic acid which can be recrystallized from acetic acid.

Likewise, from the respective starting compounds are prepared the following compounds: 6-isopropylsulfinylxanthone-2-carboxylic acid, 6-ethylsulfinylxanthone-2-carboxylic acid, 6-n-propylsulfinylxanthone-2-carboxylic acid, 6-n-butylsulfinylxanthone-Z-carboxylic acid, 6-sec-butylsulfinylxanthone-Z-carboxylic acid, 6-isobutylsulfinylxanthone-2-carboxylic acid, 6-t-butylsulfinylxanthone-2-carboxylic acid, 6-n-pentylsulfinylxanthone-Z-carboxylic acid, 6-cyclopropylsulfinylxanthone-2-carboxylic acid, 6-cyclobutylsulfinylxanthone-2-carboxylic acid, and 6-cyclopentylsulfinylxanthone-2-carboxylic acid.

The procedures of Examples 7 and 8 can be practiced upon the corresponding acid starting compounds to give the same products without the need of the hydrolysis step.

EXAMPLE 9 One g. of 6-mercaptoxanthone-2-carboxylic acid is dissolved in 30 ml. of acetic acid containing 3 ml. of concentrated hydrochloric acid under warming. The solution is then saturated with chlorine gas and stirred at room temperature overnight. The solution is then diluted with water and the precipitate filtered off, washed, and dried to give 6-chlorosulfonylxanthone-Z-carboxylic acid. I

The thus-prepared chlorosulfonyl compound is then treated with aqueous potassium hydroxide to give 6-sulfoxanthone-2-carboxylic acid.

EXAMPLE 10 A mixture of 1 g. of 6-chlorosulfonylxanthone-2- carboxylic acid, 2 ml. of concentrated aqueous ammonia, and 20 ml. of dioxane is stirred at room temperatureovernight. The mixture is then diluted with water,'acidified and the solid filtered off and dried to give 6esuIfamoylxanthQne-Z carboxylic acid.

Upon substituting a primary amine, such as methylnine andethylamine, or a secondary amine, such as d methylamine and diethylamine, for ammonia in the above method, the corresponding 06 N-mono- 21 lower alkylsulfamoyl and N,N-dilower alkylsulfamoyl' products are obtained, e.g.: 1 6-rnethylsulfamoylxanthonei-carboxylic acid, 6-ethylsulfamoylxanthone-2 carb'oxylic acid," 6-n-propylsulfamoylxanthohe-Z-carboxylic acid, 6-isopropylsulfamoylxanthon-Z-carboxylic acid,

fi-dimethylsulfamoylxanthorie-Z-carboxylic acid,

6-diethylsulfamoylxanthone-2-carboxylic acid, 6-di-n-propylsulfamoylxanthone-2-carboxylic acid, 6-di-isopropylsulfamoylxanthone-2-carboxylic acid, and so forth.

EXAMP-L'E if 1,3'-Dicarbomethoxy-4-bromobeniene methylthio'phenol are condensed bythe procedure'of Example 1, paragraph 1, to give l,3-,dica rbomothoxy 4-(m methylthiophenyloxy) benzene. This compound is hydrolyzed with a 5% potassiumhydroxidermethanolv solution at reflux for 1 hour to give l,3-dica rbox'y- 4-(m-methylthiophenyloxy)-benzene; The resultant compound is cyclized according to the procedure'of Example 1, paragraph' 3 to give 6-(methylthio)-xanthone-Z-carboxylic acid.

In like manner, the other 6 -(lo wer alkylthio)- xanthone-Z-carbo yIic acids and 6-chloroxanthone-2- carboxylic acid are prepared from 'the appropriate starting compounds.

The thus-prepared compounds .are' useful as described above in Examples 2, 7, and 8.

EXAMPLE i2 and my,

stirred at room temperature for a period of 6 hours. After monitoring the reaction by tlc indicates the absence of starting material; ml. of isopropanol are added and the resultant mixture warmed onthe-steam bath. Water.(2 00 ml.) isthen added portionwise to the resultant mixture which is cooled to room temperature. The precipitate is filtered off, washed, and dried to obtain methyl 6-acetylxanthone-2-carboxylate.

- A mixture .of-1.09 g. of methyl 6-acetylxanthone- Z-carboxylate, 70 ml. of isopropanol, 5 ml. of saturated sodium carbonate solution, and 25 ml. of water is refluxed for 2 hours. The resultant mixture is then acidified, cooledand the crystals filtered off, washed, and dried to give 6-, acetylxanthone-2-carboxylic acid. The foregoing procedures .can be followed with .other 6-substituted methyl compounds (prepared according to the procedures of Example 12) to give the corresponding 6-acyl compounds, to wit: 6-propionylxanthone-2-carboxylic acid, 6-n-butyrylxanthone-2-carboxylic acid, 6-isobutyrylxanthone-2-carboxylic acid, 6-n-pentanoylxantho ne-2-carboxylic acid, 6-isopentanoylxanthone-2-carboxylic acid, 6-sec-pentanoylxanthone-2-carboxylic acid, 6 -t-pentanoylxanthone-2-carboxylic acid, 6 -n-hexanoylxanthone-2-carboxylic acid, q

',.6-cyclopropylcarbonylxanthone-Z-carboxylic acid,

The methyl esters thereofare prepared as described in Example4. g I

EXAMPLE is, A mixture of 4 g. of ethy lxanthone-2 carboxylic acid, 10 g. of methyl iodide, and 10g, of potassium carbonate in ml. ofrdimethylformamide is stirred at room temperature fora period "of l6'hours. After this period of 'time,the reaction mixture is poured into dilute hydrochloric acid-ice'and' the resultant mixture extracted with ethyl acetat'ejThe extracts are filtered through aluminato give methyl 6-ethylxanthone-Z-carboxylate which'can' be' recrystalliz ed from methanol. ,7 p 7 p v A suspension of 2,5 g.,of methyl 6-ethylxanthorie-2- carboxylate and 2.5 g. of chromic oxide in 190 ml.

of acetic acid and 10 ml. of acetic anhydride is 6-cyclobutylcarbonylxanthotre-Z-caiboxylic acid, and 6-cyclopentylcarbonylxanthone 2-carboxylic acid.

' EXAM LE .14

A mixture of 1.077 g. of methyl 6-acetylxanthone- 2-carboxylate, 200 mg. of sodium borohydride and 150 ml. of tetrahydrofuran is stirred for 2.5 hours at room temperature. The reaction is monitored by tlc. After this period of time, a 5%"aqueous acetic acid solution is added to the reaction mixture dropwise to neutrality and the resultant solution evaporated under vacuum and crystallized by the addition of ethanol and hot water. The precipitate is filtered off,

washed and dried to give methyl 6-(l-hydroxyethyhxanthone-Z-carboxylate. j

A mixture of 860 mg. of methyl 6- (1-hydroxyethyl) xantlib'ne-Z-carboxylate, ml. of ethanol and 2 ml. of 2N sodium hydroxide is refluxed for 30 minutes. The resultant mixture is cooled, acidified and the precipitate is filtered off, washed,and dried to give 6 (1-hydroxyethyl)-xanthone-2 carboxylic acid.

The'foregoing procedures are practiced upon the otherjG-acyl methyl esters prepared as describedii'l Example 13 to give the following products, through their respective methyl esters:

6-(1 hydroxy-n-prOpy'D Xanthone-Z-carboxylic' acid,

6-(1-hydroxy-n-butyD-xanthone-Z-carboxylic acid, 6%(1-hydroxy-isobutyl)-xanthone-2-carboxylic acid, 6-(1' hydroxy-n pentyD anthone-2gcarboxylic acid, 6-(1-hydroxy-isopentyl)-xantlione-2-carboxylic acid, 6-(1 hydroxy-sec-pentyl)QXanthbne-Z-carboxylic acid, 6-(1Ehydroxy-t pentyh xanthonei-carboxylic acid, 6-("1-hydroxy-n-hexyl) xanthone 2-carboxylic acid,

6-((cyclopropyl)hydroxymethyl) xanthone-2 carboxyliC BQCid,

, 6-((cyclobutyl)hydroxymethyl)-xanthone-2-carboxylic f cidfln X I 6-((cyclopentyl)hydroxymethyl)-xanthone-2-carboxylic acid.

EXAMPLE m-Methoxyphenol and the methyl diester of 4- bromo-1,3-dicarboxy benzene are condensed and hydrolyzed to 4-(m-methoxyphenyloxy)-1,3-dicarboxybenzene according to the procedure of Example 1. This compound is then cyclized (Example 1, paragraph 3) to give 6-methoxyxanthone-2-carboxylic acid to which is useful as described in Example 3 et seq.

EXAMPLE l6 A mixture of 51.5 g. of 1,3-dimethyl-4-iodobenzene (4-iodo-m-xylene), 40 g. of m-methylthiophenol, 16 g. of cuprous oxide in 300 ml. of dimethylacetamide is heated to the boiling point and maintained under reflux (190C) for 144 hours with stirring and under a nitrogen atmosphere. The reaction mixture is then poured into ice water and extracted with ether and the extracts are filtered through 500 g. of alumina in hexane to give 1,3-dimethyl-4-(m-chlorophenyloxy)- benzene.

A mixture of 41 g. of 1,3-dimethyl-4-(m-chlorophenyloxy)-benzene, 300 g. of potassium permanganate, 500 ml. of t-butanol, and 750 ml. of water isv heated to the boiling point and maintained thereat for a period of three hours. After distilling off the tbutanol, the reaction mixture is filtered, the clear filtrate acidified and the precipitate of 1,3-dicarboxy- 4-(m-chlorophenyloxy)-benzene is isolated by suction filtration and washed with water.

The l,3-dicarboxy-4-(m-chlorophenyloxy)-benzene thus prepared is then cyclized as described in Example 1 or 17 to give 6-(chloroxanthone)-2-carboxylic acid.

EXAMPLE 17 A mixture of 1,3-dimethyl-4-bromobenzene, 10.5 g. of m-methoxyphenol, 4.65 g. of cuprous oxide, 40 ml. of tetramethylurea, and 75 ml. of N-methylpyrrolidone is stirred at 165 for 96 hours. The resultant mixture is diluted with water and extracted with methylene chloride. The methylene chloride extracts are chromatographed on 300 g. of alumina with gradient elution using hexanezether to give 1,3,- dimethyl-4-(m-methoxyphenyloxy)-benzene.

A mixture of 12 g. of 1,3-dimethyl-4- (m-methoxyphenyloxy)-benzene, 72 g. of potassium permanganate, 200 ml. of t-butanol and 350 ml, of water is refluxed for 4% hours. After this time, the t-butanol is distilled off, and the reaction mixture is filtered. The filtrate is acidified to give 1,3-dicarboxy-4-(m-methoxyphenyloxy)-benzene which can berecrystallized from benzeneiheptane.

A mixture of 3 g. of 1,,3-dicarboxy-4-(m-methoxyphenyloxy)-benzene, 75 ml. of polyphosphoric acid,

- and 75 ml. of sulfolane is stirred at 125C for a period of two hours. After this time, the reaction mixture is poured into water, filtered and the precipitate washed. The precipitate is recrystallized from acetic acid (charcoal) to give 6-methoxyxanthone-Z-carboxylic acid which can be converted to S-hydroxyxanthone- 2-carboxylic acid.

In a similar manner, the foregoing procedure can be practiced utilizing other m-lower alkoxyphenol crystallized from methanol.

starting compounds to prepare the corresponding products, for example, 6-ethoxyxanthone-Z-carboxylic acid, 6-n-propoxyxanthone-2-carboxylic acid, 6-isopropoxyxanthone-2-carboxylic acid,

6-n-butoxyxanthone-2-carboxylic acid, and so forth, which can each be converted to 5-hydroxyxanthone-2-carboxylic acid.

EXAMPLE 18 An ice-cooled solution of 5 grams of acetanilide and 15 g. of aluminum chloride in ml. of dichloroethane is treated with 5 g. of benzoyl chloride in portions. The mixture is then heated at C for three hour s,decomposed with ice and dilute hydrochloric acid and the resulting solid isolated by suction filtration and recrystallized from ethanolzwater to give pbenzoylacetanilide.

p-Benzoylacetanilide (2.8 g.) and ml. of 1N hydrochloric acid are refluxed for six hours. After cooling, the solution is made alkaline by the addition of 2N sodium hydroxide solution and extracted with ether to give 4-aminobenzophenone, which is re- Bromine (5.5 g.) is added dropwise to a stirred solution of 6.75 g. of 4-aminobenzophenone in ml. of chloroform. After the addition is complete, stirring is continued for 30 minutes. Dilute sodium bicarbonate solution is added and the mixture is extracted with chloroform. The resulting bromo derivative can be recrystallized from methanol.

4-Amino-3-brornobenzophenone (11.4 g.) is suspended in a hot mixture of 10 ml. of concentrated hydrochloric acid and 10 ml. of water. After cooling the mixture to 0C, a solution of 3.0 g. of sodium nitrite in 10 ml. of water is added dropwise. To the resulting clear solution of the diazonium chloride, a solution of 6 g. of sodium fluroborate in 10 ml. of water is added with vigorous stirring. The precipitate is isolated by suction filtration, washed successively with 5% fluroboric acid, methanol, and ether and left to dry in the air.

Acetic acid (15 ml.) is added dropwise to a cooled solution of 2.5 q. of the diazonium fluroborate in 25 ml. nickel carbonyl. The mixture is then concentrated in vacuo and diluted with water. The precipitated 4- benzoyl-Z-brorho-benzoic acid is collected "on a sintered glass filter and recrystallized from ethanol.

The resultant compound is esterified as described in Example 4 and then reacted with methyl p-hydroxybenzoate as described in Example 16, first paragraph, followed by hydrolysis (Example 5, last paragraph) and cyclization (Example 1, last paragraph) to give 6 -benzoylxanthone 2-carboxylic acid. The later can be reduced (Example 14, first paragraph) to give 6- ((phenyl)hydroxymethyl)-xanthone-2-carboxylic acid.

In like manner, the following are prepared: 6-propionylxanthone-2-carboxylic acid; 6-n-butyrylxanthone-2-carboxylic acid; 6-isobutyrylxanthone-Z-carboxylic acid; 6-n-pentanoylxanthone-Z-carboxylic acid; 6-isopentanoylxanthone-2-carboxylic acid; 6-sec-pentanoylxanthone-2-carboxylic acid; 6-t-pentanoylxanthone12-carboxylic acid;

25 6-n-hexanoylxanthone-2-carboxylic acid; 6-n-heptanoylxanthone-2-carboxylic acid; 6-n-octanoylxanthone-2 carboxylic acid; 6-n-nonanoylxanthone-Z-carbdxylic acid; 6-cyclopropylcarbonylxanthone-2-carboxylic acid; 6-cyclobutylcarbonylxanthone-2-carboxylic acid; -cyclopentylcarbonylxanthone-Z-carboxylic acid; 6-cyclohexylcarbonylxanthone-2-carboxylic acid; 6-trifluoroacetylxanthone-2-carboxylic acid; 6-difluoroacetylxanthone Z-carboxylic acid; 6-trichloroacetylxanthone-2-carboxylic acid; 6-dichloroacetylxanthone-2-carboxylic acid; 6-(p-chlorobenzoyl)-xanthone-2-carboxylic acid; 6-(p-methylbenzoyl)-xanthone-2-carboxylic acid; 6-(p-methoxybenzoyl)-xanthone-2-carboxylic acid; 6-(p-thiomethoxybenzoyl)-xanthone-2-carboxylic acid; 6-furoylxanthone-2-carboxylic acid; 6-pyrroylxanthone-2-carboxylic acid; 6-thenoylxanthone-2-carboxylic acid; 6-pyridylcarbonylxanthone-Z-carboxylic acid; 6-imidazolylcarbonylxanthone2-carboxylic acid; and 6-oxazo1ylcarbonylxanthone-2-carboxy1ic acid; and

thence: 6-(1-hydroxy-ti-propyl)-xanthone-2-carboxylic acid; 6-( 1 -hydroxy-n-buty1)-xanthone-2-carboxylic acid; 6-(1-hydroxyisobutyD-xanthone-Z-carboxylic acid; 6-(1'-hydroxy-n-pentyD-xanthone-2-carboxylic acid; 6(1hydroxyisopenty1)-xanthone-2-carboxylic acid;

6-(1-hydroxy-sec-pentyl)-xanthone-2-carboxylic acid;

6-(1-hydroxy-t-pentyl)-xanthone-2-carboxylic acid; 6(1-hydroxy n-hexyl)-xanthone-2carboxylic acid; 6-(1-hydroxy-n-heptyl)-xanthone-2-carboxy1ic acid; 6-(1-hydroxy-n-octyl)-xanthone-Z-carboxylic acid; 6-(1-hydroxy-n-nonyD-xanthone-Z-carboxylic acid; 6-((cyclopropyl)hydroxymethyl)-xanthone-2-carboxylic acid; 6-((cycl0butyl)hydroxymethyl)-xanthone-2-carboxylic acid; 6-((cyclopentyl)hydroxymethyl)-xanthone-2-carboxylic acid; I 6-((cyclohexyl)hydroxymethyD-xanthone-Z-carboxylic acid; 6-(2 ,2 ,Z-trifluoro- 1 -hydroxyethyl)-xanthone-2-carboxylic acid; 6-(2 ,Z-difluoro-1-hydroxyethyl)-xanthone-2-carboxylic acid; 6-(2,2,2-trichloro-l-hydroxyethyl)-xanthone-2-carboxylic acid; 6(2,2-dichloro-1 hydroxyethylyxanthone-2-carboxylic acid; 6-((p-chlorophenyl)hydroxymethyD-xanthone-2-carboxylic acid; 6-((p-methylphenyl)hydroxymethyl)-xanthone-2-carboxylic acid; 6-((p-methoxyphenyl)hydroxymethyD-xanthone-Z- carboxylic acid; 6-((p-thiomethoxyphenybhydroxymethyl)-xanthone- 2-carboxylic acid; 6-((furyl)hydroxymethyl)-xanthone-2-carboxylic acid; 6-((pyrryl)hydroxymethyl)-xanthone-2 carboxylic acid; 6-((thienyl)hydroxymethyD-xantho acid; M 6-((pyridyDhydroxymethyl)xanthonef2rcarboxylic acid;

-.carboxylic 26 6-((imidazolyl)hydroxymethyl)-xanthone-Z-carboxylic acid; and 6-((oxazolyl)hydroxymethyl)-xanthone-2-carboxylic acid.

EXAMPLE l9 Methyl 6-methylxanthone-2-carboxylate is prepared by the procedure of Example 1] from mmethylphenol.-

To a solution of 2.4 g. of methyl 6-methylxanthone- Z-carboxylate in 30 ml. acetic acid and 30 ml. acetic anhydride are added 4.8 ml. concentrated sulfuric acid, the mixture is stirred for five hours. The crude diacetoxymethyl intermediate is isolated by diluting the reaction mixture with water and filtering off the precipitate. The formyl derivative is obtainedby refluxing the diacetoxymethyl compound thus obtained with 10 ml. of 2N sulfuric acid in 90ml. methanol for minutes, cooling, diluting with 60 ml. water and filtering off the precipitate to give 6-formylxanthone- 2-carboxylic acid. This compound can be reduced as described above to 6-hydroxymethylxanthone-Z- carboxylic acid. v

EXAMPLE 20 A mixture of 2 g. of 6-(l-hydroxyethyl)-xanthone- 2-carboxylic acid in 8 ml. of pyridine and 4 ml. of acetyl chloride is heatedat steam bath temperatures for one hour. The mixture is then poured into HCl/ice water and the solid which forms is collected by filtration, washed with water and dried to yield 6-(1- acetoxyethyl)xanthone-2-carboxylic acid.

Upon substitution of the appropriate acyl chloride in the above procedure and, in addition, employing as starting compounds the products listed in Example 14, the following compounds are prepared: 6-(1-propionyloxyethyl)-xanthone-2 carboxylic acid, 6-( l -butyryloxyethyl)-xanthone-2-carboxylic acid,

6-( l -pentanoyloxyethyl)-xanthone-2-carboxylic acid, 6-( l -acetoxy-n-propyl)-xanthone-2-carboxylic acid, 6-(1-propionyloxy-n-propyl)-xanthone-2-carboxylic acid, and so forth, 6-(1-acetoxy-n-butyl)-xanthone-2-carboxylic acid, 6-(1-pr0pionyloxy-n-butyl)-xanthone-2-carboxylic acid, and so forth, 6-(1-acetoxyisobutyl)-xanthone-2-carboxylic acid, I 6-(1-propionyloxyisobutyl)-xanthone-2-carboxylic acid, and so forth, 6-((cyclopropyDacetoxymethyl)-xanthone-2-carboxylic acid, and so forth, 5 s 6-((phenyDacetoxymethyl)-xanthone-2-carboxylic acid, and so forth.

EXAMPLE 21 To a mixture of 2.5 g. of methyl 6-(l-hydroxyethyl)- xanthone-2-carboxylate and 500 mg. of sodium hydride in 45 ml. of dimethylformamide is added 2 ml. of methyl iodide and the mixture is stirred at room temperature for 16 hours. The mixture is then poured into dilute HCl/ice water, filtered and dried to give methyl 7-(l-methoxyethyl)-xanthone-2-carboxylate.

The resultant product is hydrolyzed according to the procedure of the last Paragraph of Example 5 to give Upon substitution of the appropriate alkyl or cycloalkyl iodide or bromide and, in addition, employing as starting compounds the products listed in Example 14, the following compounds are prepared, through their respective esters: 6-(1-ethoxyethyl)-xanthone-Z-carboxylic acid,

6( l -n-propoxyethyl)-xanthone-2-carboxylic acid. 6-(1-butoxyethyl)-xanthone-2-carboxylic acid, 6-(1-n-pentyloxyethyl)-xanthone-2-carboxylic acid, 6(1isopropoxyethyl)-xanthone-2-carboxylic acid, 6-(1 -isobutoxyethyl)-xanthone-2-carboxylic acid, 6(l-cyclopentyloxyethyl)-xanthone-2carboxylic acid, 6( 1-cyclopropyloxyethyl)-xanthone-2-carboxylic acid, 6(1-methoxy-n-propyl)-xanthone-2-carboxylic acid, 6( l -methoxy-n-butyl)-xanthone-2-carboxylic acid, 6-(1-methoxyisobutyl)xanthone-2-carboxylic acid, 6((cyclopropyl)methoxymethyl)-xanthone-2- carboxylic acid, 6((cyclopropyl)ethoxymethyl)-xanthone-2-carboxylic acid, 6-((phenyl)methoxymethyl)xanthone-2-carboxylic acid, and 6-((phenyDethoxymethyl)-xanthone-2-carboxylic acid.

EXAMPLE 22 EXAMPLE 23 Ten milliliters of dihydropyran are added to a solution of 1 g. of methyl 6-(1-hydroxyethyl)-xanthone-2- carboxylate in 50 ml. of benzene. About '1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for four days, and is then washed with aqueous sodium carbonate solution and Water, dried and evaporated. The residue is crystallized from chloro form/methanol/pyridine to yield methyl 6-(1-tetrahydropyran-Z-yloxyethyl)-xanthone-2-carboxylate.

Hydrolysis provides 6-(1-tetrahydropyran-2'- yloxyethyl)-xanthone-2-carboxylic acid.

By use of dihydrofuran in the above procedure, 6(]- tetrahydrofuran-2-yloxyethyl)-xanthone-2-carboxylic acid is prepared.

In like manner, the following compounds are prepared:

6-(1 -tetrahydropyran-2 -yloxy-n-propyl) xanthone-Z-carboxylic acid, 6-(1-tetrahydropyran-2-yloxy-isobutyl-xanthone- 2-carboxylic acid, 6(1-tetrahydropyran-2-yloxy-nbutyl)-xanthone- 2-carboxylic acid, and the tetrahydrofuran-2- yloxy compounds corresponding thereto. 3.5 Grams of methyl 6(1-hydroxyethyl)-xanthone Z-carboxylate in 150 ml. of benzene and 500 mg. of p-toluene-sulfonic acid (dried by azeotropic distillation from benzene) are mixed together and the reaction mixture is treated with 4-methoxy-5, 6-dihydro-ZH-pyran, 1 ml. at a time until reaction is complete (followed by tlc). The reaction is quenched by addition of 1/2 ml. of triethylamine, washed with water, and crystallized with care from methanol containing pyridine to give methyl 6-(1-4-methoxytetrahydropyran-4'-yloxyethyl)-xanthone-2carboxylate.

Hydrolysis provides 6-(1-4-methoxytetrahydropyran-4yloxyethyl)-xanthone-2-carboxylic acid.

A solution of 1.4 g. of aluminum chloride in 25 ml. of tetrahydrofuran is treated with a solution of 0.4 g. of lighium aluminum hydn'de in 100 ml. of ether. Methyl 6-(1-4-methoxy-tetrahydropyran-4-xyloxyethyl)-xanthone-2-carboxylate (500 mg.) is extracted into the solution. After reduction is complete (monitored by tlc), saturated sodium chloride is added until a precipitate forms. This is filtered and the crude product is oxidized in acetic acid using excess sodium dichromate to give 6-(1-tetrahydropyran-4yloxyethyl)xanthone-2-carboxylic acid.

In like manner, the following compounds are prepared: 6(1-4-methoxytetrahydropyran-4-yloxy-n-propyl)- xanthone-2-carboxylic acid, 6-(1-tetrahydropyran-4-yloxy-n-propyD-xanthone- 2-carboxylic acid,

6-(1 -4 ethoxytetrahydropyran-4 -yloxyethyl)- xanthone-Z-carboxylic acid,

6-(1-4-methoxytetrahydropyran-4yloxyisobutyl)- xanthone-Z-carboxylic acid, and

6( l-4-propoxytetrahydropyran-4-yloxy-npropyl)-xanthone-2-carboxylic acid.

EXAMPLE 24 A mixture of 4.5 grams of 6-methylsulfinylxanthone-Z-carboxylic acid, 10 g. of methyl iodide, and 10 g. of lithium carbonate in m1. of dimethylformamide is stirrred at room temperature for a period of 18 hours. After this period of time, the reaction mixture is poured into dilute hydrochloric acid-ice and the resultant precipitate is filtered off and washed to give methyl 6-methylsulfinyl-xanthone-2-carboxylate.

The foregoing procedureis repeated using the alternate lower alkyl iodides so as to prepare the corresponding lower alkyl acid esters hereof, e.g. ethyl 6-methylfulfinylxanthone-2-carboxylate, n-propyl 6-methylsulfinylxanthone-Z-carboxylate,

vopropyl 6-methylsulfinylxanthone-Z-carboxylate, n ropyl 6methylsulfinylxanthone-Z-carboxylate, isv utyl 6-methylsulfinylxanthone-2-carboxylate,

EXAMPLE 25.

To a solution of g. of 6- methylsulfinylxanthone- 2-carboxylic acid in 200 ml. of ethanolis addedthe theoretical amount of sodium hyroxide dissolved in 200 ml. of 90% ethanol. The reaction mixture is then concentrated in vacuum to give sodium 6-methylsulfinylxanthone-Z-carboxylate.

In a similar manner, the potassium and lithium salts are prepared. Similarly, by replacing the sodium salt by means of an appropriate metal salt reagent, e.g. calcium chloride, manganese chloride, and so forth, the other xanthone-Z-carboxylic acid salts are prepared, e.g.

magnesium 6-methylsulfinylxanthone-2-carboxylate, calcium 6-methylsulfinylxanthone-Z carboxylate, aluminum 6-inethylsulfinylxanthone-Z-carboxylate, ferrous 6-methylsulfinylxanthohe-Z-carboxylate,

zinc 6-methylsulfinylxanthone-Z-carboxylate, manganese 6-methylsulfinylxanthone-Z-carboxylate, ferric 6-methylsulfinylxanthone-Z-carboxylate, and

so forth.

In a similar manner, the xanthone-Z-carboxylic acid salts of the other 06 substituted xanthone-2- carboxylic acids hereof are prepared, e.g. potassium 6-methylsulfonylxanthone-Z-carboxylate, sodium 6- sulfamoylxanthone-Z-carboxylate, and so forth.

In the sulfo series, use of one equivalent of base provides the sulfo acid salt and use of two or more equivalents provides the disalt, e.g. 6-sulfoxanthone- Z-carboxylic acid disodium salt.

EXAMPLE 26 To a mixture of 50 ml. of concentrated aqueous ammonia in 500 ml. of methanol there are added g. of 6-sulfamoylxanth0ne-2carboxylic acid. The resultant mixture is stirred for two hours and is then evaporated to dryness to give the ammonium saltof 6-sulfamoylxanthone-2-carboxylic acid.

A solution of 10 g of 6-sulfamoylxanthone-Z-carboxylic acid in 50 ml. of thionyl chloride is heated at reflux for one hour. Thereafter, the solution is evaporated to dryness to give the corresponding acid chloride to which is added a concentrated ethereal ammonia solution. The resultant solution is evaporated giving the 6-sulfamoylxanthone-Z-carboxylic acid amide.

In like manner, the lower alkyl amides can be prepared using monoalkylamine or dialkylamine in lieu of ammonia in the above procedures. Thus prepared, e.g. are: 1 I 6-methylsulfarnoylxanthone-2-ca'rboxylic acide amide, N-methyl 6-n-propylsulfinylxanthone-Z-carboxylic acid amide, N,N-dimethyl 6-dimethylsulfamoylxanthone2-carboxylic acid amide,

N,N-diethyl 6-ethylsulfonylxanthone-Z-carboxylic acid amide,

N-ethyl 6-sulfoxanthone-2-carboxylic acid amide, N-n-propyl 6-propylsulfinylxanthone-Z-carboxylic acid amide, and so forth.

EXAMPLE 27 To a mixture of 20 g. of procaine and 500 ml. of aqueous methanol are added 20 g. of 6-methylsulfinylxanthone-2-carboxylic acid. The resultant mixture is stirred at room temperature for 16 hours. It is then evaporated under reduced pressure, to give the procaine salt of 6-methylsulfinylxanthone-2-carboxylic acid.

Similarly, the lysine, caffeine, and arginine salts thereof are obtained. In like manner, the e.g. procaine, lysine, caffeine, and arginine salts of the other 6- substituted xanthone-2-carboxylic acids are obtained, e.g. the procaine salt of 6-ethylsulfonylxanthone-Z- carboxylic acid, the caffeine salt of 6-propylsulfinylxanthone-Z-carboxylic acid, the. lysinesalt of 6-di-t-butylsulfamoylxanthone-Z-carboxylic acid, the

procaine salt of 6-sec-butylsulfinylxanthone-2-carboxylic acid, and the arginine salt of6-sulfoxanthone- Z-carboxylic acid.

EXAMPLE 28 EXAMPLE 29 The following procedure illustrates a test procedure for the compounds hereof.

Normal female (Sprague-Dawley) rats of to 200 grams each are passively sensitized intradermally by injection of rat anti-egg albumin reaginic sera. After 24 hours, each rat is challenged intravenously with a 1 ml. of 0.5% Evans blue, 1 mg. egg albumin plus 0.20 mg. of 6-methylsulfinylxanthone-2-carboxylic acid. Control rats receive no 6-methylsulfinylxanthone-Z-carboxylic acid. The dermal bluing is recorded 15 to 25 minutes later. The rats which receive the 6-methylsulfinylxanthone-2-carb oxylic acid exhibit a 100 percent inhibition of allergic reaction whereas the control rats exhibit no inhibition.

The above procedure is repeated using 6-methylsulfinylxanthone-Z-carboxylic acid, with similar results. The above procedure is repeated using oral administration, with similar results. a

The C-6 substituted xanthone-Z-carboxylic acid compounds are administered by gavage at a dose of mg. per animal minutes prior to challenge. Twenty to thirty minutes after challenge the degree of dermal bluing is read, with similar results.

Inhibition of 'reaginic antigen-antibody reactions in rats is regarded as representative of inhibition of human reaginic antigen-antibody reactions which occur during allergic episodes.

Subjects challenged by antigen inhalation are measured for the extent of provoked degree of asthma condition by changes in airway resistance on expiration. The subject compounds are administered as an aerosol by inhalation before antigen challenge.

'Prevention of asthmatic conditions upon the administration of the compounds is evidenced by a decrease in airway resistance and other, subjective improvements, e.g. reduced cough.

CLAIMS What is claimed is: 1. A compound selected from those represented by the following formula:

coon

and the pharmaceutically acceptable, non-toxic esters, amides and salts thereof; wherein R is a group selected from those'of the formula i H-R wherein R is hydrogen, lower alkyl, cycloalkyl, tetrahydrofuran-Z-yl, tetrahydropyran-2-yl, tetrahyl5 dropyran-4-yl, 4-alkoxytetrahydropyran-4-yl, or carboxylic acyl containing up to 12 carbon atoms, and R is hydrogen; lower alkyl; cycloalkyl; phenyl; substituted phenyl, in which the substituent is halo, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl,

O or cyano.

2. The compound according to claim 1 of the formula:

6 coon I I l R IH wherein R is as defined in claim 1 and R is hydrogen, methyl or acetyl.

3. The compound according to claim 2 wherein R is hydrogen and R is methyl; 6 -(l-hydroxyethy1)- 

1. A COMPOUND SELECTED FROM THOSE REPRESENTED BY THE FOLLOWING FORMULA:
 2. The compound of the group defined in claim 1 which is 2-(N-phenylbenzylamino)-1-pyrroline hydrochloride.
 3. The compound of the group defined in claim 1 which is 2-(N-phenylbenzylamino)-1-pyrroline.
 4. The compound of the group defined in claim 1 which is 5-methyl-2-(N-phenylbenzylamino)-1-pyrroline hydrochloride.
 5. The compound of the group defined in claim 1 which is 5-methyl-2-(N-phenylbenzylamino)-1-pyrroline.
 6. The compound of the group defined in claim 1 which is 5,5-dimethyl-2-(N-phenylbenzylamino)-1-pyrroline hydrochloride.
 7. The compound of the group defined in claim 1 which is 5,5-dimethyl-2-(N-phenylbenzylamino)-1-pyrroline.
 8. The compound of the group defined in claim 1 which is 2-(N-(m-trifluoromethylphenyl)benzylamino)-1-pyrroline hydrochloride.
 9. The compound of the group defined in claim 1 which 2-(N-(m-trifluoromethylphenyl)benzylamino)-1-pyrroline.
 10. The compound of the group defined in claim 1 which is 2-(3, 4-dichloro-N-(2-thenyl)anilino)-5-methyl-1-pyrroline hydrochloride.
 11. The compound of the group defined in claim 1 which is 2-(3, 4-dichloro-N-(2-thenyl)anilino)-5-methyl-1-pyrroline.
 12. The compound of the group defined in claim 1 which is 5,5-dimethyl-2-(N-(m-trifluoromethylphenyl)benzylamino)-1-pyrroline hydrochloride.
 13. The compound of the group defined in claim 1 which is 5,5-dimethyl-2-(N-(m-trifluoromethylphenyl)benzylamino)-1-pyrroline.
 14. The compound of the group defined in claim 1 which is 3,4,5, 6-tetrahydro-2-(N-phenylbenzylamino)pyridine and the pharmaceutically acceptable acid addition salts thereof.
 15. The compound of the group defined in claim 1 which is 3,4,5, 6-tetrahydro-7-(N-phenylbenzylamino)-2H-azepine and the pharmaceutically acceptable acid addition salts thereof.
 16. The compound of the group defined in claim 1 which is 2-(N-(o-methoxyphenyl)benzylamino)-1-pyrroline and the pharmaceutically acceptable acid addition salts thereof.
 17. The compound of the group defined in claim 1 which is 2-(N-(3,4-dichlorophenyl)benzylamino)-1-pyrroline and the pharmaceutically acceptable acid addition salts thereof.
 18. The compound of the group defined in claim 1 which is 5-methyl-2-(N-(m-trifluoromethylphenyl)benzylamino)-1-pyrroline and the pharmaceutically acceptable acid addition salts thereof.
 19. The compound of the group defined in claim 1 which is 2-(N-phenylphenethylamino)-1-pyrroline And the pharmaceutically acceptable acid addition salts thereof.
 20. The compound of the group defined in claim 1 which is 5-methyl-2-(phenylphenethylamino)-1-pyrroline and the pharmaceutically acceptable acid addition salts thereof.
 21. The compound of the group defined in claim 1 which is 5,5-dimethyl-2-(N-phenylphenethylamino)-1-pyrroline and the pharmaceutically acceptable acid addition salts thereof.
 22. The compound of the group defined in claim 1 which is 3,4,5, 6-tetrahydro-7-((N-phenyl)phenethylamino)-2H-azepine and the pharmaceutically acceptable acid addition salts thereof.
 23. The compound of the group defined in claim 1 which is 3,4,5, 6,7,8-hexahydro-2-(N-phenylphenethylamino)azocine and the pharmaceutically acceptable acid addition salts thereof.
 24. The compound of the group defined in claim 1 which is 4,5,6, 7,8,9-hexahydro-2-(N-phenylphenethylamino)-3H-azonine and the pharmaceutically acceptable acid addition salts thereof.
 25. The compound of the group defined in claim 1 which is 2-(3-chloro-N-furfurylanilino)-5,5-dimethyl-1-pyrroline and the pharmaceutically acceptable acid addition salts thereof.
 26. The compound of the group defined in claim 1 which is 2-(N-phenylphenethylamino)-1-aza-1-cyclotridecene and the pharmaceutically acceptable acid addition salts thereof. 